Performance of cardiac surgery is a delicate and invasive procedure. The majority of epicardial bypass graft surgeries, and all open heart procedures, require temporary arrest of the heart to allow the surgeon to accomplish the required task without interference from heart movement. An extracorporeal machine, known as a cardiopulmonary bypass (CPB) circuit, assumes the heart and lungs' role of supplying oxygenated blood to the rest of the body while the heart is arrested. Once the surgery is completed, the heart must be re-started, and the patient weaned from the CPB.
While the use of CPB makes cardiac surgery feasible, it is also associated with significant risks and difficulties. The use of a CPB machine usually requires an aortic cross-clamp to separate the heart from the rest of the circulation. Because the coronary arteries arise very close to the heart, the cross clamp must be applied distal to their ostia and therefore they receive no blood flow for prolonged periods, and thus the heart becomes ischemic. Despite numerous myocardial protection strategies, such as hypothermia and chemical cardioplegia to decrease oxygen consumption by arresting the heart, many patients' heart function is significantly impaired by both chemical arrest and the CPB circuit itself. Chemical cardioplegia, altered coronary perfusion, embolic events and direct manual manipulation of the heart during the procedure all contribute to depression of myocardial function after it is restarted. Furthermore, the degree of post CPB dysfunction may depend on the duration of the CPB time. Patients emerge from chemical cardiac arrest with a spectrum of left ventricular dysfunction, from transient mild impairment to outright ventricular failure and inability to be separated from the CPB. Patients with preexisting ventricular dysfunction are at the greatest risk for further myocardial impairment during CPB.
Moreover, because of improvements in surgical technique and intraoperative myocardial protection, as well as the increasing availability of sophisticated valvular, direct myocardial resections, repairs of septal defects, and coronary bypass procedures, more cardiac operations are being performed on patients with more advanced stages of disease and decreased ventricular function. Indeed, the number of operative risk factors, including advanced age, female gender, severity of angina, triple vessel disease, and left ventricular dysfunction, has increased among patients currently undergoing coronary artery bypass surgery [Davis P K, et al., Ann Thorac Surg 1989; 47:493-98].
In addition, there are important, potentially damaging effects of CPB itself on the cardiovascular system, including increased capillary permeability with attendant transcapillary plasma loss, renal dysfunction, peripheral or central vasoconstriction, coagulopathy, platelet destruction and dysfunction, and destruction of red blood cells [Kalter R D, et al., .J Thorac Cardiovasc Surg 1979; 77:428-35; Kirklin J K, et al., J. Thorac Cardiovasc Surg 1983; 86:845-57.]. Patients with preexisting cardiomyopathies are at even greater risk for postoperative contractile dysfunction. These effects are often transient, but their timing and intensity can make it difficult to impossible in many instances to separate the patient from the CPB circuit.
Weaning a patient off cardiopulmonary bypass (CPB) is a critical step of cardiac surgical procedures. Restarting the heart and returning it and the lungs to the circulation after CPB carries the potential to severely stress an already compromised heart. In the best of circumstances, weaning off CPB can be a relatively straightforward process that requires reestablishing ventilation to the lungs and slowly lowering the circulatory support from the CPB pump. In a significant number of cases however, weaning is especially difficult, and in a few situations simply impossible.
Current available options to support patients who fail to wean from CPB, in order of increasing invasiveness and associated morbidity, include intravenous infusion of inotropes that enhance myocardial contractility, insertion of an intra-aortic balloon pump to augment coronary perfusion and diminish the workload on the heart, and placement of a ventricular assist device. However, each of these treatments is accompanied by significant morbidity and technical limitations, and potential toxicity. Examples of limitations associated with such treatments include proarrhythmic and systemic effects from systemic infusion of inotropes, damage from large-bore indwelling vascular access, need for patient immobility and sedation, as well as risks associated with the placement of a large mass of foreign materials with externalized connections. The pumps and devices have high rates of infection and thromboembolic complications, and require patient immobility, sedation, sometimes prolonged postoperative ventilation, and the most extreme of intensive care nursing support. Weaning of small children after prolonged, difficult and complex operations can represent a further challenge to the surgical team as assist devices may not be readily available in appropriate sizes.
One of the significant challenges of supporting patients as they transition from CPB to the intensive care unit is the variability between patients regarding the timing and degree of support each patient requires. Many patients only need short-term inotropic support to help them transition from CPB to the intensive care unit, while the support required by other patients is much more extensive and potentially associated with greater risks. Thus, it would be desirable to have less intrusive means that could be used to support these patients as they transition off CPB.
Inotropic agents are one approach used to enhance a high-risk patient's ability to wean from CPB. Pharmacologic inotropic agents enhance myocardial contractility, and fall into two broad categories: sympathomimetics such as epinephrine (adrenaline), norepinephrine (noradrenaline), dobutamine, isopreterenol, salbutamol, salmeterol, terbutaline, isoproterenol, phenylephrine, ephedrine, clonidine and dopamine, and phosphodiesterase inhibitors such as milrinone and amrinone. Each of these compounds, while increasing the inotropic state of the heart, has limitations that restrict the doses that can be given intravenously and often necessitate infusion of additional agents to counteract side effects. For example, dopamine dosing is limited by the increase in the rate and irritability of electrical excitation of the heart that accompanies the desired inotropic effect. Alternatively, phosphodiesterase inhibitors increase intracellular cyclic AMP, an intracellular signaling molecule that increases inotropy, but unfortunately dilates arterioles and causes systemic vasodilation and hypotension. As a result, vasoconstricting sympathomimetic agents often need to be co-administered and these again can lead to proarrythmogenic states and undesirable tachycardia.
One important consideration of the use of inotropic agents is that they are administered systemically and thus treat all vascular beds. Systemic side effects of sympathomimetics include potential renal and cerebral vasoconstriction, and pulmonary artery hypertension, which in turn can induce right heart failure. Other undesired effects are excess tachycardia and electrical irritability.
Accordingly, there is a need for improved methods to support patients as they transition off CPB, by improving contractile function of the heart without extraventricular effects, such as tachycardia, vasoconstriction or systemic hypotension.